Summary: Data obtained from experimental malaria models show that immunization with irradiated malaria sporozoites or repeated infections and drug cure with asexual stage parasites protect the host against live parasite infection. Furthermore, the fact that adults in malaria endemic areas develop immunity against clinical disease suggests that it is feasible to develop a vaccine against malaria parasite. However, the immune mechanism(s) that provide protection against parasite infection is not clearly understood. It is the belief of many malaria vaccine researchers that understanding the mechanism of protective immunity is critical to develop an effective anti-malaria vaccine. We have recently developed a recombinant sub-unit vaccine that when delivered in an effective adjuvant protects mice against Plasmodium yoelii sprorozoite challenge. The murine malarias are excellent models to elucidate the complex immune mechanisms where both antibody and cellular responses contribute to immunity. Infection with murine malaria P. yoelii causes a non-lethal infection in mice. Previous work by us and by other laboratories has clearly defined the genetic background of mice that is found to most suitable for P. yoelii-challenge studies. In this project, we will perform experiments that would lead to understand the mechanism of recombinant vaccine induced protective immune responses that protect mice against sporozoite challenge. This is being accomplished by in vivo T cell and cytokine depletions in normal immnized and by immunizations in T cell, B cell, IFN-gamma, and IL-12 knockout mice.